I have already acquired a strong formation in bone biology during my graduate studies and while pursuing my postdoctoral training with Dr. Karsenty at Columbia University. My short-term goals are to pursue for the next year my training and research program as a postdoctoral scientist at Columbia University and to deepen my experience in the field of metabolism and physiology. I next anticipate applying for an independent position in a US institution to develop my own research program and to compete for grant (R01) from NIH. My mentor Dr. Karsenty is a prominent scientist in the fields of bone and endocrinology, and has effectively mentored several junior researchers. Thus I expect from this environment a broad and complete training. The objective of the K99 mentored phase of this proposal is to understand the role of bone resorption as a regulator of glucose homeostasis. We have identified osteocalcin a hormone produced by the osteoblasts, the bone forming cells, as a previously uncharacterized regulator of insulin secretion and insulin sensitivity. Importantly osteocalcin exist in two forms in mouse and human: ?-carboxylated and undercarboxylated. Only undercarboxylated osteocalcin harbors hormonal activity. We have demonstrated recently that one mechanism by which osteocalcin is decarboxylated and activated is during bone resorption by osteoclasts. This suggested that osteoclast, the bone-resorbing cell, might also play an important role in the control of energy metabolism. Thus, the first aim of this application is to determine the implication of osteoclasts in glucose metabolism by generating a mouse model characterized by a reduced number of osteoclasts. The second aim of this proposal is to study and characterize how a specific transcription factor implicated in the regulation of bone resorption can potentially affect whole body glucose homeostasis through it expression in osteoclasts. The goal of the R00 independent phase of this application is to understand how ?-carboxylation, a process requiring vitamin K can regulate glucose homeostasis. This question will be addressed by two specific aims. First I am proposing to generate mouse model deficient in ?-carboxylation in bone only, by deleting the genes encoding the only known enzymes required for this process. These mutant animals should present a very low level of carboxylated osteocalcin and I will address how this situation impacts on insulin secretion and glucose metabolism. Finally, I am planning to address the role played by vitamin K and ?-carboxylation in the cells of the pancreatic islets. Here I will generate conditional knockout mice lacking ?-carboxylation in the whole pancreas or in specific endocrine cells and verify the impact on whole body glucose homeostasis. The last two aims should lead to the discovery and characterization of unexpected functions of vitamin K and ?- carboxylation. Overall, the research proposed in this application should results in a better understanding of the processes implicated in the regulation of glucose homeostasis. This may eventually lead to the development of new treatments for metabolic disorders, including type 2 diabetes. PUBLIC HEALTH RELEVANCE: The goal of this research proposal is to acquire a better understanding of the biological processes regulating the secretion of insulin and the control of blood glucose. This could potentially lead to new therapeutic approach for the treatment of diabetes and obesity.